RESEARCH ARTICLE
Hypothyroidism and Glaucoma in The United States Caitlin Kakigi1, Toshimitsu Kasuga1,2, Sophia Y. Wang1, Kuldev Singh3, Yoshimune Hiratsuka2, Akira Murakami2, Shan C. Lin1* 1 Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States of America, 2 Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan, 3 Department of Ophthalmology, Stanford University, Stanford, California, United States of America * [email protected]
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Abstract Purpose OPEN ACCESS Citation: Kakigi C, Kasuga T, Wang SY, Singh K, Hiratsuka Y, Murakami A, et al. (2015) Hypothyroidism and Glaucoma in The United States. PLoS ONE 10(7): e0133688. doi:10.1371/journal. pone.0133688 Editor: Sanjoy Bhattacharya, Bascom Palmer Eye Institute, University of Miami School of Medicine;, UNITED STATES Received: May 11, 2014
To investigate the association between hypothyroidism and glaucomatous disease.
Methods This cross-sectional study included all subjects above the age of 40 years from two nationwide surveys: the 2008 National Health Interview Survey (NHIS) as well as the 2007 and 2008 National Health and Nutrition Examination Survey (NHANES). The presence or absence of glaucoma, thyroid disease and other demographic and health-related information including comorbidities was ascertained via interview. Blood samples were collected from NHANES subjects and analyzed for thyrotropin (TSH).
Accepted: July 1, 2015
Results
Published: July 31, 2015
A total of 13,599 and 3,839 NHIS and NHANES participants respectively were analyzed to assess for a possible relationship between self-reported glaucoma, and self-reported hypothyroidism as well as self-reported thyroid disease. The unadjusted odds ratio (OR) for NHIS showed a significant association between self-reported glaucoma and self-reported hypothyroidism (OR 1.46, 95% confidence interval [CI] 1.07-1.99). Multivariate logistic regression analysis adjusted for age, gender, race, comorbidities, and health-related behavior, however, showed no association between self-reported glaucoma and hypothyroidism or thyroid disease in both surveys (OR 1.60, 95%CI 0.87-2.95 for NHIS; OR 1.05, 95%CI 0.59-1.88 for NHANES).
Copyright: © 2015 Kakigi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All NHANES and NHIS files are publicly available from the CDC website at http://www.cdc.gov/nchs/nhanes/nhanes_ questionnaires.htm and http://www.cdc.gov/nchs/nhis/ nhis_questionnaires.htm, respectively. Funding: This work was supported by NIH-NEI EY002162 - Core Grant for Vision Research; That Man May See, Inc (http://thatmanmaysee.org/); and Research to prevent Blindness.(http://www.rpbusa. org/rpb/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conclusion A previously reported association between hypothyroidism and glaucomatous disease was not confirmed in two large U.S. health survey populations. While such an association was noted in the univariate analysis for the NHIS survey, such a relationship was not found in the multivariate analysis after adjustment for potential confounding variables.
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
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Hypothyroidism and Glaucoma in The United States
Competing Interests: The authors have declared that no competing interests exist.
Introduction There have been conflicting reports regarding whether or not hypothyroidism is independently associated with the incidence or prevalence of open angle glaucoma (OAG). Since Hertel’s initial report of two hypothyroidism patients whose intraocular pressure (IOP) was lower after thyroid hormone replacement therapy [1], there have been supportive cases and case series presented by several other groups.[2–8] In contrast, several other reports have shown no association between hypothyroidism and OAG.[9–11] The underlying hypothesis for why hypothyroidism may be an independent risk factor for OAG is based upon the belief that the low metabolic condition caused by this condition results in reduced enzymatic activity that adversely impacts aqueous humor dynamics. A change in the normal cycle of production and degradation of some enzymatic substrates is postulated to result in homeostatic changes that cause increased deposition of hyaluronic acid in the trabecular meshwork resulting in decreased aqueous outflow and a consequent higher IOP.[2,8] At least five population-based studies have been analyzed for a possible association between thyroid abnormalities and glaucoma.[12–16] Two such studies reported a positive association between hypothyroidism and the likelihood of having OAG [12,15] and others showed an association between thyroid disease and glaucoma.[14,16] One study, however, showed no association between hypothyroidism and OAG.[13] It remains controversial whether or not hypothyroidism is an independent risk factor for the development or progression of OAG. There have been no population-based studies which have evaluated the possible association between hypothyroidism and OAG based on laboratory confirmation in the form of serum levels of thyroid hormone. The present study evaluates data from two U.S. nationwide population-based surveys—the National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES)—to further investigate a potential association between hypothyroidism and open angle glaucoma with an arm including laboratory-based confirmation of hypothyroidism.
Materials and Methods Ethics statement The current study used de-identified publicly available data and was exempt from human subjects review.
Surveys The data used for this study were obtained from the 2008 National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES) for 2007 and 2008. Both NHIS and NHANES provide important health related information regarding the civilian non-institutionalized population of the United States and represent major components of the data collection programs administered by the National Center for Health Statistics (NCHS), which is part of the Centers for Disease Control and Prevention (CDC). In NHIS, one sample adult from each family is randomly selected and information on each person’s demographics and health are collected via questionnaire. NHANES, by contrast, is a combination of interviews and physical examinations, which include blood tests. NHANES 2007–2008 oversampled persons 60 and older, African Americans, and Hispanics in an effort to accumulate representative health information regarding the non-institutionalized, civilian U.S. population. Details regarding the conduct of NHIS and NHANES including study design, methods and questionnaires are available online.[17,18]
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
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Hypothyroidism and Glaucoma in The United States
NHIS The 2008 NHIS included 29,370 adults (aged 18 years or greater) who were eligible for the sample adult questionnaire of whom 21,781 completed the interviews for a response rate of 74.2%. Our study included 13,599 participants in the 2008 NHIS who were 40 years or older, and completed the adult component of the study. All adult study participants were asked to report whether or not they had ever been told by a physician or other health care professional that they had glaucoma or hypothyroidism. Participants in whom such data could not be ascertained either due to lack of knowledge or unwillingness to share this health care information were excluded from this study. Classification regarding the presence or absence of glaucoma and hypothyroidism was based solely on participants’ self-reported information. Demographic information including age, gender, and race as well as other health information was also collected and used in the analysis.
NHANES A total of 10,149 subjects participated in NHANES 2007 and 2008. We included 3,839 participants who were 40 years or older and completed both the interview and examination portions of the NHANES, and excluded all others. All study participants were asked to report whether or not they had ever been told that they had glaucoma or thyroid disease by a physician or other healthcare professional. Blood samples were collected from participants and analyzed for thyrotropin (TSH). Further details on the laboratory analysis protocol for this study can be found on the NHANES website.[19] Participants’ demographic information and other health related data were collected similar to the NHIS portion of this study. The major difference was that NHANES, but not NHIS, had an examination portion of the survey.
Variable Definitions The primary outcome variable for both analyses was the self-reported diagnosis of glaucoma. The primary predictor was thyroid disease also based upon self-reporting. In NHIS, the question upon which this self-reporting was based specifically asked whether or not the participant had been told that they had hypothyroidism, while for NHANES the question was posed to determine whether or not the participant had thyroid disease which could be manifest as either hyper- or hypothyroidism. In an effort to account for the undiagnosed cases of hypothyroidism, we performed an additional analysis based on serum TSH levels reported in the NHANES dataset. The secondary predictor for the NHANES was defined as the diagnosis of hypothyroidism confirmed by laboratory values of thyroid-related hormone levels or ascertainment of whether or not study subjects were taking medication for hypothyroidism. Participants who had laboratory-confirmed hyperthyroidism or were taking a prescription medication for hyperthyroidism were excluded from the control group. Information pertaining to drug prescriptions was obtained by interview. Such prescriptions in NHANES study subjects included levothyroxine, methimazole and propylthiouracil. The laboratory-confirmed hypothyroidism patients were further divided into two groups based upon whether or not they were taking medication for hypothyroidism to test the additional hypothesis that levothyroxine may have a protective effect against the development of glaucomatous disease.
Diagnosis of thyroid condition based on laboratory data for NHANES For the diagnosis of hypothyroidism we utilized the laboratory reference range for thyroid stimulating hormone (TSH) which was 0.34–5.60 mIU/L based on the manufacturer’s studies using non-parametric analysis of the results measured in 217 human serum samples from
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
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Hypothyroidism and Glaucoma in The United States
apparently healthy male and female subjects with normal thyroid profiles.[19] We considered subjects as ‘hypothyroid’ if their TSH was >5.60 mIU/L or they were taking levothyroxine. Subjects with TSH < 0.34 mIU/L or they were taking prescription for hyperthyroidism were considered to be ‘hyperthyroid’ and excluded from further analysis. Normal thyroid function was defined as the absence of a history of hypo- or hyperthyroidism in those not taking any medication related to a thyroid condition.
Statistical Analysis For both the NHIS and the NHANES populations, we compared the distribution of possible confounding factors between participants with and without self-reported glaucoma using design-adjusted Rao-Scott Pearson-type chi-square and Wald tests for categorical and continuous variables, respectively. Multiple logistic regressions were performed to assess the association between those self-reporting glaucoma and thyroid disease, adjusting for sociodemographic factors such as age, gender, race, education, and family income, health related behaviors such as alcohol consumption and tobacco use, comorbid medical conditions, and self-reported general health condition. In accordance with Motsko et al.[13] and Lin et al.[15], the following medical conditions were considered as potential confounders to be included in the multivariate analysis: diabetes, lipid metabolism disorders, hypertension, cardiovascular disease, cerebrovascular disease, arterial disease, and migraines. Potential confounding comorbidities which were found to be significant at the P
Hypothyroidism and Glaucoma in The United States Caitlin Kakigi1, Toshimitsu Kasuga1,2, Sophia Y. Wang1, Kuldev Singh3, Yoshimune Hiratsuka2, Akira Murakami2, Shan C. Lin1* 1 Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States of America, 2 Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan, 3 Department of Ophthalmology, Stanford University, Stanford, California, United States of America * [email protected]
a11111
Abstract Purpose OPEN ACCESS Citation: Kakigi C, Kasuga T, Wang SY, Singh K, Hiratsuka Y, Murakami A, et al. (2015) Hypothyroidism and Glaucoma in The United States. PLoS ONE 10(7): e0133688. doi:10.1371/journal. pone.0133688 Editor: Sanjoy Bhattacharya, Bascom Palmer Eye Institute, University of Miami School of Medicine;, UNITED STATES Received: May 11, 2014
To investigate the association between hypothyroidism and glaucomatous disease.
Methods This cross-sectional study included all subjects above the age of 40 years from two nationwide surveys: the 2008 National Health Interview Survey (NHIS) as well as the 2007 and 2008 National Health and Nutrition Examination Survey (NHANES). The presence or absence of glaucoma, thyroid disease and other demographic and health-related information including comorbidities was ascertained via interview. Blood samples were collected from NHANES subjects and analyzed for thyrotropin (TSH).
Accepted: July 1, 2015
Results
Published: July 31, 2015
A total of 13,599 and 3,839 NHIS and NHANES participants respectively were analyzed to assess for a possible relationship between self-reported glaucoma, and self-reported hypothyroidism as well as self-reported thyroid disease. The unadjusted odds ratio (OR) for NHIS showed a significant association between self-reported glaucoma and self-reported hypothyroidism (OR 1.46, 95% confidence interval [CI] 1.07-1.99). Multivariate logistic regression analysis adjusted for age, gender, race, comorbidities, and health-related behavior, however, showed no association between self-reported glaucoma and hypothyroidism or thyroid disease in both surveys (OR 1.60, 95%CI 0.87-2.95 for NHIS; OR 1.05, 95%CI 0.59-1.88 for NHANES).
Copyright: © 2015 Kakigi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All NHANES and NHIS files are publicly available from the CDC website at http://www.cdc.gov/nchs/nhanes/nhanes_ questionnaires.htm and http://www.cdc.gov/nchs/nhis/ nhis_questionnaires.htm, respectively. Funding: This work was supported by NIH-NEI EY002162 - Core Grant for Vision Research; That Man May See, Inc (http://thatmanmaysee.org/); and Research to prevent Blindness.(http://www.rpbusa. org/rpb/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conclusion A previously reported association between hypothyroidism and glaucomatous disease was not confirmed in two large U.S. health survey populations. While such an association was noted in the univariate analysis for the NHIS survey, such a relationship was not found in the multivariate analysis after adjustment for potential confounding variables.
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
1 / 14
Hypothyroidism and Glaucoma in The United States
Competing Interests: The authors have declared that no competing interests exist.
Introduction There have been conflicting reports regarding whether or not hypothyroidism is independently associated with the incidence or prevalence of open angle glaucoma (OAG). Since Hertel’s initial report of two hypothyroidism patients whose intraocular pressure (IOP) was lower after thyroid hormone replacement therapy [1], there have been supportive cases and case series presented by several other groups.[2–8] In contrast, several other reports have shown no association between hypothyroidism and OAG.[9–11] The underlying hypothesis for why hypothyroidism may be an independent risk factor for OAG is based upon the belief that the low metabolic condition caused by this condition results in reduced enzymatic activity that adversely impacts aqueous humor dynamics. A change in the normal cycle of production and degradation of some enzymatic substrates is postulated to result in homeostatic changes that cause increased deposition of hyaluronic acid in the trabecular meshwork resulting in decreased aqueous outflow and a consequent higher IOP.[2,8] At least five population-based studies have been analyzed for a possible association between thyroid abnormalities and glaucoma.[12–16] Two such studies reported a positive association between hypothyroidism and the likelihood of having OAG [12,15] and others showed an association between thyroid disease and glaucoma.[14,16] One study, however, showed no association between hypothyroidism and OAG.[13] It remains controversial whether or not hypothyroidism is an independent risk factor for the development or progression of OAG. There have been no population-based studies which have evaluated the possible association between hypothyroidism and OAG based on laboratory confirmation in the form of serum levels of thyroid hormone. The present study evaluates data from two U.S. nationwide population-based surveys—the National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES)—to further investigate a potential association between hypothyroidism and open angle glaucoma with an arm including laboratory-based confirmation of hypothyroidism.
Materials and Methods Ethics statement The current study used de-identified publicly available data and was exempt from human subjects review.
Surveys The data used for this study were obtained from the 2008 National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES) for 2007 and 2008. Both NHIS and NHANES provide important health related information regarding the civilian non-institutionalized population of the United States and represent major components of the data collection programs administered by the National Center for Health Statistics (NCHS), which is part of the Centers for Disease Control and Prevention (CDC). In NHIS, one sample adult from each family is randomly selected and information on each person’s demographics and health are collected via questionnaire. NHANES, by contrast, is a combination of interviews and physical examinations, which include blood tests. NHANES 2007–2008 oversampled persons 60 and older, African Americans, and Hispanics in an effort to accumulate representative health information regarding the non-institutionalized, civilian U.S. population. Details regarding the conduct of NHIS and NHANES including study design, methods and questionnaires are available online.[17,18]
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
2 / 14
Hypothyroidism and Glaucoma in The United States
NHIS The 2008 NHIS included 29,370 adults (aged 18 years or greater) who were eligible for the sample adult questionnaire of whom 21,781 completed the interviews for a response rate of 74.2%. Our study included 13,599 participants in the 2008 NHIS who were 40 years or older, and completed the adult component of the study. All adult study participants were asked to report whether or not they had ever been told by a physician or other health care professional that they had glaucoma or hypothyroidism. Participants in whom such data could not be ascertained either due to lack of knowledge or unwillingness to share this health care information were excluded from this study. Classification regarding the presence or absence of glaucoma and hypothyroidism was based solely on participants’ self-reported information. Demographic information including age, gender, and race as well as other health information was also collected and used in the analysis.
NHANES A total of 10,149 subjects participated in NHANES 2007 and 2008. We included 3,839 participants who were 40 years or older and completed both the interview and examination portions of the NHANES, and excluded all others. All study participants were asked to report whether or not they had ever been told that they had glaucoma or thyroid disease by a physician or other healthcare professional. Blood samples were collected from participants and analyzed for thyrotropin (TSH). Further details on the laboratory analysis protocol for this study can be found on the NHANES website.[19] Participants’ demographic information and other health related data were collected similar to the NHIS portion of this study. The major difference was that NHANES, but not NHIS, had an examination portion of the survey.
Variable Definitions The primary outcome variable for both analyses was the self-reported diagnosis of glaucoma. The primary predictor was thyroid disease also based upon self-reporting. In NHIS, the question upon which this self-reporting was based specifically asked whether or not the participant had been told that they had hypothyroidism, while for NHANES the question was posed to determine whether or not the participant had thyroid disease which could be manifest as either hyper- or hypothyroidism. In an effort to account for the undiagnosed cases of hypothyroidism, we performed an additional analysis based on serum TSH levels reported in the NHANES dataset. The secondary predictor for the NHANES was defined as the diagnosis of hypothyroidism confirmed by laboratory values of thyroid-related hormone levels or ascertainment of whether or not study subjects were taking medication for hypothyroidism. Participants who had laboratory-confirmed hyperthyroidism or were taking a prescription medication for hyperthyroidism were excluded from the control group. Information pertaining to drug prescriptions was obtained by interview. Such prescriptions in NHANES study subjects included levothyroxine, methimazole and propylthiouracil. The laboratory-confirmed hypothyroidism patients were further divided into two groups based upon whether or not they were taking medication for hypothyroidism to test the additional hypothesis that levothyroxine may have a protective effect against the development of glaucomatous disease.
Diagnosis of thyroid condition based on laboratory data for NHANES For the diagnosis of hypothyroidism we utilized the laboratory reference range for thyroid stimulating hormone (TSH) which was 0.34–5.60 mIU/L based on the manufacturer’s studies using non-parametric analysis of the results measured in 217 human serum samples from
PLOS ONE | DOI:10.1371/journal.pone.0133688 July 31, 2015
3 / 14
Hypothyroidism and Glaucoma in The United States
apparently healthy male and female subjects with normal thyroid profiles.[19] We considered subjects as ‘hypothyroid’ if their TSH was >5.60 mIU/L or they were taking levothyroxine. Subjects with TSH < 0.34 mIU/L or they were taking prescription for hyperthyroidism were considered to be ‘hyperthyroid’ and excluded from further analysis. Normal thyroid function was defined as the absence of a history of hypo- or hyperthyroidism in those not taking any medication related to a thyroid condition.
Statistical Analysis For both the NHIS and the NHANES populations, we compared the distribution of possible confounding factors between participants with and without self-reported glaucoma using design-adjusted Rao-Scott Pearson-type chi-square and Wald tests for categorical and continuous variables, respectively. Multiple logistic regressions were performed to assess the association between those self-reporting glaucoma and thyroid disease, adjusting for sociodemographic factors such as age, gender, race, education, and family income, health related behaviors such as alcohol consumption and tobacco use, comorbid medical conditions, and self-reported general health condition. In accordance with Motsko et al.[13] and Lin et al.[15], the following medical conditions were considered as potential confounders to be included in the multivariate analysis: diabetes, lipid metabolism disorders, hypertension, cardiovascular disease, cerebrovascular disease, arterial disease, and migraines. Potential confounding comorbidities which were found to be significant at the P
